Genome-wide analysis yields new loci associating with aortic valve stenosis

Anna Helgadottir; Gudmar Thorleifsson; Solveig Gretarsdottir; Olafur A Stefansson; Vinicius Tragante; Rosa B Thorolfsdottir; Ingileif Jonsdottir; Thorsteinn Bjornsson; Valgerdur Steinthorsdottir; Niek Verweij; Jonas B Nielsen; Wei Zhou; Lasse Folkersen; Andreas Martinsson; Mahyar Heydarpour; Siddharth Prakash; Gylfi Oskarsson; Tomas Gudbjartsson; Arnar Geirsson; Isleifur Olafsson; Emil L Sigurdsson; Peter Almgren; Olle Melander; Anders Franco-Cereceda; Anders Hamsten; Lars Fritsche; Maoxuan Lin; Bo Yang; Whitney Hornsby; Dongchuan Guo; Chad M Brummett; Gonçalo Abecasis; Michael Mathis; Dianna Milewicz; Simon C Body; Per Eriksson; Cristen J Willer; Kristian Hveem; Christopher Newton-Cheh; J Gustav Smith; Ragnar Danielsen; Gudmundur Thorgeirsson; Unnur Thorsteinsdottir; Daniel F Gudbjartsson; Hilma Holm; Kari Stefansson

doi:10.1038/s41467-018-03252-6

Genome-wide analysis yields new loci associating with aortic valve stenosis

Nat Commun. 2018 Mar 7;9(1):987. doi: 10.1038/s41467-018-03252-6.

Authors

Anna Helgadottir¹, Gudmar Thorleifsson², Solveig Gretarsdottir², Olafur A Stefansson², Vinicius Tragante², Rosa B Thorolfsdottir², Ingileif Jonsdottir^{2

3}, Thorsteinn Bjornsson², Valgerdur Steinthorsdottir², Niek Verweij^{4

5}, Jonas B Nielsen⁶, Wei Zhou⁷, Lasse Folkersen^{8

9}, Andreas Martinsson¹⁰, Mahyar Heydarpour¹¹, Siddharth Prakash¹², Gylfi Oskarsson¹³, Tomas Gudbjartsson¹⁴, Arnar Geirsson¹⁵, Isleifur Olafsson¹⁶, Emil L Sigurdsson^{17

18}, Peter Almgren^{19

20}, Olle Melander^{19

20}, Anders Franco-Cereceda²¹, Anders Hamsten⁸, Lars Fritsche^{22

23}, Maoxuan Lin⁶, Bo Yang^{24

25}, Whitney Hornsby²⁵, Dongchuan Guo¹², Chad M Brummett²⁶, Gonçalo Abecasis²⁷, Michael Mathis²⁶, Dianna Milewicz^{12

28}, Simon C Body¹¹, Per Eriksson⁸, Cristen J Willer^{6

7

25

29}, Kristian Hveem^{22

23}, Christopher Newton-Cheh^{5

30

31}, J Gustav Smith¹⁰, Ragnar Danielsen^{3

32}, Gudmundur Thorgeirsson^{2

3

32}, Unnur Thorsteinsdottir^{2

3}, Daniel F Gudbjartsson^{2

33}, Hilma Holm², Kari Stefansson^{34

35}

Affiliations

¹ deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. anna.helgadottir@decode.is.
² deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland.
³ Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
⁴ Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands.
⁵ Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.
⁶ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, 48109, MI, USA.
⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA.
⁸ Cardiovascular Medicine Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, 17176, Sweden.
⁹ Department of Bioinformatics, Technical University of Denmark, Copenhagen, 2800, Denmark.
¹⁰ Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, 22185, Sweden.
¹¹ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
¹² Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston, Houston, 77030, TX, USA.
¹³ Childrens Hospital, Landspitali National University Hospital of Iceland, Reykjavik, 101, Iceland.
¹⁴ Department of Surgery and Cardiothoracic Surgery, Landspitali National University Hospital, Reykjavik, 101, Iceland.
¹⁵ Section of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, 06510, CT, USA.
¹⁶ Department of Clinical Biochemistry, Landspitali National University Hospital, Reykjavik, 101, Iceland.
¹⁷ Heilsugaeslan Solvangi, Hafnarfjördur, 220, Iceland.
¹⁸ Department of Family Medicine, University of Iceland, Reykjavik, 101, Iceland.
¹⁹ Department of Clinical Sciences, Lund University, Malmö, 22185, Sweden.
²⁰ Department of Internal Medicine, Skåne University Hospital, Malmö, 22185, Sweden.
²¹ Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, 17176, Sweden.
²² HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, 7491, Norway.
²³ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, 7491, Norway.
²⁴ Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI, 48105, USA.
²⁵ Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁶ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, 48105, USA.
²⁷ Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁸ Medicine Services, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, TX, 77030, USA.
²⁹ Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
³⁰ Massachusetts General Hospital, Harvard Medical School, Broad Institute of Harvard and MIT, Boston, MA, 02114, USA.
³¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
³² Department of Internal Medicine, Division of Cardiology, Landspitali National University Hospital of Iceland, Reykjavik, 101, Iceland.
³³ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101, Iceland.
³⁴ deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. kstefans@decode.is.
³⁵ Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. kstefans@decode.is.

Abstract

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10^-22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10^-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10^-10) and aortic root diameter (P = 1.30 × 10^-8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10^-3) and coronary artery disease (OR = 1.05, P = 9.3 × 10^-5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Aortic Valve Stenosis / genetics*
Case-Control Studies
Coronary Artery Disease / genetics
Genome-Wide Association Study
Humans
Phenotype
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding